<p>Severe sepsis leads to damage of multiple organs, among which the lung is the most commonly damaged organ, yet its underlying mechanisms and therapeutic strategies are incompletely understood. Western blot and Immunohistochemistry analyses were performed to detect expression levels of related genes. HE staining was used to assess the severity of lung injury. Transmission electron microscopy (TEM) was employed to explore morphological alterations in cells. The C11 BODIPY 581/591 kit was used to detect the lipid peroxidation activity. Differentially expressed potential key genes of sepsis-induced acute lung injury (ALI) were screened out through GEO database mining, among which Lipocalin 2 (LCN2) played the most important role in the development of ALI, and mechanistic studies confirmed that LCN2 aggravated sepsis-induced ALI by inhibiting MUC1 to activate ER-stress-autophagy induced ferroptosis via lactate/MCT1/AMPK/mTOR axis. Finally, molecular docking technology was used to identify sorafenib as a potential therapeutic compound for ALI based on LCN2. Further studies showed that sorafenib improved the survival rate of septic mice and alleviated lung injury. This study revealed the key pathogenic role and underlying mechanisms of LCN2 in sepsis-induced ALI, and provided sorafenib as one of new targets and therapeutic strategies.</p>